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Biomarkers for CDK4/6 Inhibitors

Panelists: Adam M. Brufsky, MD, University of Pittsburgh Cancer Institute; Ahmad Awada, MD, PhD, Jules Bordet Institute; Wolfgang J. Janni, MD, PhD, University of Ulm; Hope S. Rugo, MD, UCSF Helen Diller Family Comprehensive Cancer Center; Michael Untch, MD, Helios Klinikum Berlin-Buch
Published: Tuesday, Jan 03, 2017


Transcript:

Adam M. Brufsky, MD, PhD:
One thing that we always thought in all of these trials is, ‘Well, maybe there will be a biomarker for response in these to CDK4 inhibitors.’ And, I know, at ESMO, you’re going to present data on biomarkers. Are there biomarkers that respond to CDK4 inhibitors?

Hope S. Rugo, MD: So, Rich Finn did a really excellent oral presentation on the biomarker analysis from PALOMA-2, and it’s really nice. I definitely encourage people to look at those slides from ESMO that look at a whole bunch of different things—including the cyclin D, and retinoblastoma (Rb), and a bunch of other markers—and even look at differential response based on extent of ER positivity. It does look like there is no biomarker. It worked in everybody just like it worked in young and old people and visceral and non-visceral, etc. It’s just there is not a biomarker that predicts response. There has been, although certainly not covered in that presentation, the idea that if you have a mutated Rb, that CDK inhibitors don’t work. But, that is a tiny percentage of patients with ER-positive metastatic breast cancer. So, it doesn’t seem to matter. It’s just so frustrating that we have so much trouble finding biomarkers. We haven’t found one for everolimus either. They did a presentation at ASCO looking at circulating cell-free DNA and couldn’t find anything there.

Ahmad Awada, MD, PhD: This is a general comment. We are looking always for biomarker of sensitivity, and we agree that it is difficult task. Then, why not look for a biomarker of resistance to therapy? It’s easier. We had an example in a clinical practice. In colorectal cancer, RAS-mutated tumors didn’t respond to anti-EGFR therapy. There are some that say some mutations in androgen receptors that seems not to respond to hormone therapy in prostate cancer. So, I think, honestly, we should possibly try, at least, to reverse and look for…And that’s more important for the patient, not to give them a toxic drug and a costly drug.

Adam M. Brufsky, MD, PhD: Absolutely. Michael, do you have any comments?

Michael Untch, MD: I would like to make a universal comment on this last topic. I have the feeling, and I would like to share the thoughts with you, that in the metastatic breast cancer setting, HER2-negative hormone receptor-positive, with all these new molecules, we’re now in the situation where we can delay or skip chemotherapy for metastatic disease, number 1. Number 2, I saw yesterday a very nice presentation given by Sara Hurvitz on the combination of a CDK4/6 inhibitor with an aromatase inhibitor. It was neoadjuvant, for hormone receptor-positive disease with very nice, not clinical, data, but decreasing Ki67, which is a very good surrogate for response. But, I would like to see the clinical data now. So, the old dream was skip chemotherapy in early breast cancer, also for metastatic breast cancer. Is it going to come through?

Hope S. Rugo, MD: I think that’s really exciting. I have to say that the idea, and Cynthia Ma and Matt Ellis’s work in the neoadjuvant setting also, have been very encouraging. There are the abemaciclib data from here at ESMO with Sara Hurvitz, and Cynthia Ma presented some data with palbociclib in the neoadjuvant setting. And she is also running the ALTERNATE trial looking at just hormone therapy. But, the whole goal being that at 2 weeks, or 4 weeks, the drop in Ki67 cell cycle arrest is a predictor that we can use, just like it drops when you stop hormone replacement therapy. What would be cool about that, I think, is that you could take patients who have endocrine-sensitive disease and really decide who needs chemotherapy or not based on that in vivo response. I think that would be really interesting.

Adam M. Brufsky, MD, PhD: Well, let me ask you a question. A few biomarkers that may be helpful, do we think that ESR1 mutations eventually will be useful for us in the clinic going forward?

Ahmad Awada, MD, PhD: As a biomarker, you mean?

Adam M. Brufsky, MD, PhD: Using an AI versus a future... So, someone is on anastrozole for 2 years.

Ahmad Awada, MD, PhD: My understanding is that this mutation appears to be following several hormonal therapies, endocrine therapies. And so, the need here is to have a new approved, new therapeutic approach to deal with that. Yes, I think this is a really important population. From my understanding, from what is reported, is that is 30% of the patients.

Adam M. Brufsky, MD, PhD: 30% on AIs.

Ahmad Awada, MD, PhD: They develop receptor-mutated tumors. There are many drugs under investigation now. And so, I think here, we are looking for a new approach, new drugs, rather than the drugs we have currently.

Hope S. Rugo, MD: I think that some of the hypotheses of the FALCON trial was really that in those patients who have very endocrine-sensitive disease who are going to stay on hormone therapy for a while, using fulvestrant may delay the onset of ESR1 mutation. That’s a hypothesis because they’ll have to look at the FALCON patients to see.

Michael Untch, MD: My simple answer is yes. Second, we need more data and let’s do some more trials.

Adam M. Brufsky, MD, PhD: I agree.

Transcript Edited for Clarity
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Transcript:

Adam M. Brufsky, MD, PhD:
One thing that we always thought in all of these trials is, ‘Well, maybe there will be a biomarker for response in these to CDK4 inhibitors.’ And, I know, at ESMO, you’re going to present data on biomarkers. Are there biomarkers that respond to CDK4 inhibitors?

Hope S. Rugo, MD: So, Rich Finn did a really excellent oral presentation on the biomarker analysis from PALOMA-2, and it’s really nice. I definitely encourage people to look at those slides from ESMO that look at a whole bunch of different things—including the cyclin D, and retinoblastoma (Rb), and a bunch of other markers—and even look at differential response based on extent of ER positivity. It does look like there is no biomarker. It worked in everybody just like it worked in young and old people and visceral and non-visceral, etc. It’s just there is not a biomarker that predicts response. There has been, although certainly not covered in that presentation, the idea that if you have a mutated Rb, that CDK inhibitors don’t work. But, that is a tiny percentage of patients with ER-positive metastatic breast cancer. So, it doesn’t seem to matter. It’s just so frustrating that we have so much trouble finding biomarkers. We haven’t found one for everolimus either. They did a presentation at ASCO looking at circulating cell-free DNA and couldn’t find anything there.

Ahmad Awada, MD, PhD: This is a general comment. We are looking always for biomarker of sensitivity, and we agree that it is difficult task. Then, why not look for a biomarker of resistance to therapy? It’s easier. We had an example in a clinical practice. In colorectal cancer, RAS-mutated tumors didn’t respond to anti-EGFR therapy. There are some that say some mutations in androgen receptors that seems not to respond to hormone therapy in prostate cancer. So, I think, honestly, we should possibly try, at least, to reverse and look for…And that’s more important for the patient, not to give them a toxic drug and a costly drug.

Adam M. Brufsky, MD, PhD: Absolutely. Michael, do you have any comments?

Michael Untch, MD: I would like to make a universal comment on this last topic. I have the feeling, and I would like to share the thoughts with you, that in the metastatic breast cancer setting, HER2-negative hormone receptor-positive, with all these new molecules, we’re now in the situation where we can delay or skip chemotherapy for metastatic disease, number 1. Number 2, I saw yesterday a very nice presentation given by Sara Hurvitz on the combination of a CDK4/6 inhibitor with an aromatase inhibitor. It was neoadjuvant, for hormone receptor-positive disease with very nice, not clinical, data, but decreasing Ki67, which is a very good surrogate for response. But, I would like to see the clinical data now. So, the old dream was skip chemotherapy in early breast cancer, also for metastatic breast cancer. Is it going to come through?

Hope S. Rugo, MD: I think that’s really exciting. I have to say that the idea, and Cynthia Ma and Matt Ellis’s work in the neoadjuvant setting also, have been very encouraging. There are the abemaciclib data from here at ESMO with Sara Hurvitz, and Cynthia Ma presented some data with palbociclib in the neoadjuvant setting. And she is also running the ALTERNATE trial looking at just hormone therapy. But, the whole goal being that at 2 weeks, or 4 weeks, the drop in Ki67 cell cycle arrest is a predictor that we can use, just like it drops when you stop hormone replacement therapy. What would be cool about that, I think, is that you could take patients who have endocrine-sensitive disease and really decide who needs chemotherapy or not based on that in vivo response. I think that would be really interesting.

Adam M. Brufsky, MD, PhD: Well, let me ask you a question. A few biomarkers that may be helpful, do we think that ESR1 mutations eventually will be useful for us in the clinic going forward?

Ahmad Awada, MD, PhD: As a biomarker, you mean?

Adam M. Brufsky, MD, PhD: Using an AI versus a future... So, someone is on anastrozole for 2 years.

Ahmad Awada, MD, PhD: My understanding is that this mutation appears to be following several hormonal therapies, endocrine therapies. And so, the need here is to have a new approved, new therapeutic approach to deal with that. Yes, I think this is a really important population. From my understanding, from what is reported, is that is 30% of the patients.

Adam M. Brufsky, MD, PhD: 30% on AIs.

Ahmad Awada, MD, PhD: They develop receptor-mutated tumors. There are many drugs under investigation now. And so, I think here, we are looking for a new approach, new drugs, rather than the drugs we have currently.

Hope S. Rugo, MD: I think that some of the hypotheses of the FALCON trial was really that in those patients who have very endocrine-sensitive disease who are going to stay on hormone therapy for a while, using fulvestrant may delay the onset of ESR1 mutation. That’s a hypothesis because they’ll have to look at the FALCON patients to see.

Michael Untch, MD: My simple answer is yes. Second, we need more data and let’s do some more trials.

Adam M. Brufsky, MD, PhD: I agree.

Transcript Edited for Clarity
View Conference Coverage
Online CME Activities
TitleExpiration DateCME Credits
Community Practice Connections™: CDK4/6 Inhibitors With the Experts: The Role of Emerging Agents for the Management of Metastatic Breast CancerMay 30, 20182.0
Medical Crossfire®: Clinical Updates on PARP Inhibition and its Evolving Use in the Treatment of CancersMay 30, 20181.5
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